Translational Approach to Models in Relapse

描述（由申请人提供）：药物滥用是一种慢性复发性疾病。在实验室动物中的药物复吸和人类中的药物复发之间存在关键差异。该提案的第一个目标是在非寻求治疗的人类可卡因滥用者和非人灵长类动物中开发复发的平行实验室模型。我们将通过使用行为偶然性来产生较低的可卡因摄入率，来近似临床情况，即药物摄入率开始很高（基线），然后变低（治疗），然后经常再次变高（复发）。我们将通过为参与者提供在药物和替代药物之间进行选择的机会，来模拟治疗中个人对服用药物的选择。一旦我们确定了产生低吸毒率所需的行为偶然性，第二个目标是检查单次自我服用可卡因剂量对可卡因选择的影响，即，可卡因导致的复发在治疗中，与传统的恢复模型相反，在所有测试期间，人类和非人类灵长类动物都将获得可卡因，而不是安慰剂。目标1：确定一组行为的偶然性，这将是有效的减少选择自我管理可卡因。我们将通过增加获得一剂可卡因的工作要求来增加选择可卡因的成本，我们将通过增加人类在机会游戏中赚钱的概率来增加可卡因替代品的价值，以及非人类灵长类动物的首选食物。我们假设：1）可卡因选择将随着可卡因成本的增加和可卡因使用替代品价值的增加而减少; 2）在选择阶段之前立即自我施用单剂量的“免费”可卡因（无成本或替代品）将以剂量依赖性方式增加可卡因选择的水平，即，可卡因导致的复发目标二：通过确定莫达非尼维持治疗对可卡因选择和可卡因诱导的复发的影响，为新模型提供“概念验证”，莫达非尼是一种警戒剂，已证明在治疗可卡因滥用方面具有临床效用。我们假设，莫达非尼的维持治疗将减少可卡因的选择和可卡因诱导的复发。我们将模拟复发的基本方面：非寻求治疗的人类和非人类灵长类动物将根据他们将不得不为药物工作的努力程度以及他们将不得不放弃非药物替代品的程度来决定是否开始使用药物。人类和非人类灵长类动物的平行设计将使我们能够同时完善当前的临床前实验室动物和人类复发模型，从而提高我们开发更有效的策略以减少药物使用复发的能力。

DESCRIPTION (provided by applicant): Drug abuse is a chronic relapsing disorder. Key differences exist between drug reinstatement in laboratory animals and drug relapse in humans. The first objective of this proposal is to develop parallel laboratory models of relapse in non-treatment seeking human cocaine abusers and in nonhuman primates. We will approximate the clinical situation, where rates of drug taking start off high (baseline), then become low (treatment) and then often become high again (relapse), by using behavioral contingencies to produce low rates of cocaine intake. We will model the choices made by individuals in treatment to take drug by providing participants opportunities to choose between drug and an alternative reinforcer. Once we have established the behavioral contingencies needed to produce a low rate of drug taking, the second objective is to examine the effect of a single self-administered dose of cocaine on cocaine choice, i.e., cocaine- induced relapse. As in treatment, and in contrast to traditional reinstatement models, both humans and non- human primates will have access to cocaine, not placebo, during all test sessions. Aim 1: Determine a set of behavioral contingencies that will be effective in decreasing the choice to self- administer cocaine. We will increase the cost of choosing cocaine by increasing the work requirement to obtain a dose, and we will increase the value of the alternative reinforcer to cocaine by increasing the probability of earning money in a game of chance in humans, and a preferred food treat in nonhuman primates. We hypothesize that 1) cocaine choice will decrease with increasing cocaine cost and with increasing value of the alternative to cocaine use; and 2) a single dose of "free" cocaine (available without cost or alternatives) self-administered immediately before the choice session will increase the level of cocaine choice in a dose-dependent manner, i.e., cocaine-induced relapse. Aim 2: Provide "proof of concept" for the new model by determining the effect of maintenance on modafinil, an alerting agent that has demonstrated clinical utility in treating cocaine abuse, on cocaine choice and cocaine-induced relapse. We hypothesize that maintenance on modafinil will decrease cocaine choice and cocaine-induced relapse. We will model essential aspects of relapse: non-treatment seeking humans and nonhuman primate's will make decisions to initiate drug use based on how hard they will have to work for drug and how much they will have to forego in non-drug alternatives. The parallel design for humans and nonhuman primates will allow us to simultaneously refine current preclinical laboratory animal and human models of relapse, and thereby improve our ability to develop more effective strategies for decreasing relapse to drug use.